Sphingolipids (SLs) can participate in a wide variety of cellular functions, including cell-cell interactions, cell growth and differentiation, and signal transduction. SLs can interact with cholesterol to form membrane microdomains, and data from many studies suggest that the plasma membrane (PM) SL and cholesterol composition may be tightly regulated. To achieve this regulation, cells must balance complex processes such as endocytosis, recycling, intracellular sorting, and metabolism of SLs.
Several clathrin-independent mechanisms of endocytosis have been identified and actively studied in mammalian cells. One well-studied clathrin-independent mechanism is uptake via caveolae—flask-shaped invaginations at the PM that are enriched in SLs and cholesterol and are associated with the protein, caveolin-1 (Cav1). Caveolae may be involved in the uptake and/or binding of certain viruses (e.g., SV40), toxins (e.g., cholera toxin B subunit (CtxB)), fungi, bacteria, SLs, integrins, and albumin in various cell types.
Membrane microdomains represent local regions of membranes that have a different overall composition from the bulk membrane and are thought to act as organizing centers to sequester particular lipids and proteins. Evidence for microdomains in various intracellular membranes comes from multiple approaches including “detergent insolubility” of membrane components, crosslinking of membrane proteins and lipids, biophysical studies of constrained lateral diffusion in membranes, energy transfer measurements to demonstrate “clustering” of labeled proteins in membranes, and EM studies to visualize local “enrichment” of particular proteins or lipids on membranes. Microdomain formation is thought to play a role in processes such as intracellular sorting and membrane signaling events. Caveolae (enriched in glycosphingolipids (GSLs) and cholesterol) are considered to be one type of PM microdomain.
Integrins are a family of αβ heterodimeric membrane proteins at the PM which bind to extracellular matrix proteins and cell surface ligands, and are responsible for many types of cell adhesion events. Some integrins are internalized via caveolae or are present in lipid-enriched microdomains.